U.S. Pat. No. 4,605,517 is related to a method of preparing steroid compounds of controlled particle size comprising dissolving the steroid in an organic solvent, precipitating the steroid by mixing a non-solvent for the steroid with the resulting solution, and controlling the time of mixing and the degree of agitation during mixing.
Sjoestroem et al. [J. Pharm. Sci (1993) 82(6), 584-9] describe a process for preparing small particles of sparingly water-soluble active compounds by precipitation in oil-water emulsions. For this purpose, the steroids cholesteryl acetate and β-sitosterol were dissolved in an organic solvent, and an emulsion was prepared with water in the presence of a surfactant. Evaporation of the organic solvent results in a precipitate of the steroid with particle sizes down to 25 nm.
Hem et al. [J. Pharm. Sci (1967), 56(2), 229-233] describe the mechanism of crystallization of hydrocortisone on exposure to ultrasound.
EP 142309 A2 describes the preparation of active compounds by dissolving in an organic solvent and mixing with a non-solvent for the active compound. Epostane was for this purpose dissolved in dimethylformamide (DMF), and water was added. The precipitate obtained in this way has particle sizes which are within a narrow size range.
Ruch et al. [Journal of Colloid and interface Science (2000), 229(1), 207-211] describe the preparation of budesonide particles in the micrometer size range by precipitation in an ultrasonic bath. For this purpose, water is added to budesonide solutions exposed to ultrasound until a precipitate is obtained or, in the case where budesonide is dissolved in solvent mixtures, the more volatile solvent is evaporated at room temperature.
WO 90/03782 relates to a process for preparing a finely divided solid by dissolving the solid in a liquid carrier solvent in order to form an injection solution, and adding the injection solution to an antisolvent which is a supercritical fluid, a compressed, liquefied gas or a dense vapour.
WO 92/08730 describes a process for crystallizing organic substances, especially steroids. For this purpose, the steroid is dissolved in a ternary mixture of lipophilic solvent, hydrophilic solvent and a surface-active substance, and crystallized. This is said to result in predeterminable and homogeneous particle sizes by non-mechanical means.
Ciclesonide is the INN (International Nonproprietary Name) for a compound with the chemical name 16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)pregna-1,4-diene-3,20-dione [11 beta, 16alpha(R)]. The preparation of ciclesonide and other epimeric pregna-1,4-diene-3,20-dione 16,17-acetal 21-esters with anti-inflammatory effect having a butyl, isopropyl, sec-butyl, cyclohexyl or phenyl radical on the cyclic acetal ring, and whose C-21 hydroxyl group is acylated by an acetyl or isobutyryl radical, are disclosed in DE-A 41 29 535. Isolation of the respective R epimer starting from an R/S mixture by preparative high-pressure liquid chromatography (HPLC) is described. The international patent application WO 98/09982 A1 describes a process for epimer enrichment of the R epimer of ciclesonide by fractional crystallization. For this purpose, ciclesonide in the form of an R/S mixture is dissolved in a suitable water-miscible organic solvent at the boiling point, water is added, and the mixture is cooled to room temperature. The R epimer-enriched ciclesonide obtained in this way must, however, then be subjected to a mechanical micro on in order to obtain the particle sizes and distributions necessary for inhalable pharmaceutical preparations. It would be desirable during the chemical synthesis of ciclesonide to obtain the active compound as product of the process already in form having particle sizes and distribution suitable immediately for further processing to inhalable preparations. This would make it possible to dispense with the additional mechanical micronization and thus possible disadvantages of a mechanical micronization [e.g. risk of contamination, formation of particles which are too small, increased uptake of water owing to the amorphous structures of the micronized product compared with crystalline structures] could be avoided.